The term neurodegeneration is used herein to refer to the progressive loss of nerve cells, occurring in aging and in neurodegenerative disorders, comprising but not limited to Alzheimer's, Parkinson's, Amyotrophic Lateral Sclerosis (ALS), Multiple Sclerosis and Huntington's disease, and in stroke, head and spinal trauma (Nature Rev. Mol. Cell. Biol. 1, 120 (2000)). Primarily, these diseases are characterized by chronic and progressive loss of neurons in discrete areas of the brain or the peripheral nerves, causing debilitating symptoms such as dementia, loss of memory, loss of sensory or motor capability, decreased overall quality of life and well-being, disability, and eventually, premature death. For most neurodegenerative diseases, currently there is little or no treatment; at best, treatments are symptomatic in nature and do not prevent or slow the progression of disease.
The term neuronal cell death by apoptosis is used herein to refer to the ‘end-point’ of many human neurological disorders, including but not limited to Alzheimer's, Parkinson's and Huntington's diseases, stroke/trauma, multiple and amyotrophic lateral sclerosis (Trends Neurosci 28, 670 (2006)). Apoptotic death of hippocampal and cortical neurons is responsible for the symptoms of Alzheimer's disease; death of midbrain neurons that use the neurotransmitter dopamine underlies Parkinson's disease; Huntington's disease involves the death of neurons in the striatum, which control body movements; and death of lower motor neurons manifests as amyotrophic lateral sclerosis. Additionally, brain ischemia and trauma induce necrosis of a small brain area, which then propagates neuronal cell loss by apoptosis to a larger brain area, due to the neurotoxic material released by the necrotic cells. Apoptotic neuronal cell loss is also observed in the ageing brain, as a physiological process.
The term natural neurosteroids is used herein to refer to molecules with the cholesterol backbone such as dehydroepiandrosterone (DHEA), or allopregnanolone, which are produced in the brain (Proc Natl Acad Sci USA 95, 4089 (1998)). Previous studies have shown that these endogenous, naturally occurring neurosteroids may protect neurons against cell apoptosis induced by neurotrophic factor deprivation (Proc Natl Acad Sci USA 101, 8209 (2004)). The neuroprotective, antiapoptotic effects of these neurosteroids occur at very low, nanomolar concentrations (1 nM), and are mediated by activation of specific membrane receptors and the subsequent production of anti-apoptotic Bcl-2 proteins (FASEB J 20, 577 (2006)). Furthermore, these natural neurosteroids at nanomolar concentrations stimulate the secretion and production of neuroprotective dopamine (Endocrinology 146, 3309 (2005)).
The adult central nervous system (CNS) is classically known as a structure with very limited regenerative capacity. However, several pathological conditions, e.g. ischemia, epilepsy and trauma, have been shown to upregulate neural stem cell activity in the sub-ventricular zone and the dentate gyrus. These findings suggest that signals are present throughout the adult brain, which allow limited neuronal regeneration to occur. This fundamental observation changes our view on neurodegeneration and the brain's regenerative capacity, giving us the potential ability to regenerate specific brain areas. Two naturally occurring neurosteroids (DHEA and allopregnanolone) have recently been shown to induce neurogenesis in various experimental models (Proc Natl Acad Sci USA 101, 3202 (2004) and J Neurosci 25, 4706 (2005)).
The lack of effective treatment for devastating neurodegenerative diseases has stimulated great interest in the development of neuroprotective means that can prevent or treat progressive loss of neural function leading to serious impairment and death. There is a sustained need for the development of new compounds for neural cell protection, repair and rescue, targeting neural cell apoptosis and survival or neurogenesis. Natural neurosteroids such as DHEA possess important neuro-protective and neurogenic properties in vitro and in vivo, in experimental animals. However, naturally occurring neurosteroids are metabolised in humans into estrogens, androgens or progestins which exert generalized and important endocrine side effects, including hormone-dependent neoplasias (Front Neuroendocrinol 21, 1 (2000)), thus limiting their clinical use.
GB 1,079,840 (1966) discloses 3β-hydroxy-17-spirooxyranyl-androst-5-ene as an intermediate in the synthesis of certain steroidal lactone compounds.
U.S. Pat. No. 3,320,242 (1967) discloses 17β,20-epoxy steroids and methods for their production. 17β,20-epoxy-17α-methylandrost-5-en-3β-ol (1) and 17β,20-epoxy-17α-methylandrost-4-en-3-one (2) are specifically claimed.

U.S. Pat. No. 3,300,489 (1967) discloses steroidal C-17 spirolactones and processes and intermediates used in the preparation thereof. Compounds 3 and 4 below are disclosed as intermediates.
wherein X is a single C—C bond or a methylene group.
U.S. Pat. No. 3,413,288 (1968) and U.S. Pat. No. 3,506,652 disclose a process for the production of steroidal C-17 spirolactones using as an intermediate a steroidal epoxide compound having the formula
wherein Y represents a single bond when W is a hydroxyl group.
U.S. Pat. No. 3,365,475 (1968) discloses a process for the preparation of 17α-(3′-hydroxy-propyl)-4-androstene-3β,17β-diol which is useful in the preparation of steroidal 17-spirotetrahydrofurans which possess useful therapeutic properties as aldosterone inhibitors.
U.S. Pat. No. 3,364,238 (1968) discloses 3-oxygenated spiro[androstene-17,1′-cycloprop-2′-ene] and their 2′,3′-dihydro derivatives of the structural formula
wherein R can be hydrogen or a lower alkanoyl radical, R′ and R″ can be hydrogen or a lower alkyl radical, and the dotted line indicates the optional presence of a double bond.
U.S. Pat. No. 4,026,918 (1977) describes the preparation of certain D-homosteroids that are said to have anti-inflammatory activity. (3β,11α,17α)-Spiro[androst-5-ene-17,2′-oxirane]-3,11-diol is disclosed as a chemical intermediate.
U.S. Pat. No. 4,054,563 (1977) discloses a process for the manufacture of 17-spiro-(2′-oxacyclopentane) steroid compounds of the general formula
wherein R1 represents a hydrogen atom or a lower alkyl group, which contain a double bond in the 5-position and a methyl group at the 10-position, or three double bonds in the position 1,3 and 5(10), and which can contain an additional double bond in the 9(11)-position. The compounds are said to be useful intermediates for preparing aldosterone antagonists.
WO 98/33506 discloses the use of certain compounds for inhibiting androgen synthesis, which are said to be useful in treating prostate cancer and benign prostatic hypertrophy. 17β,20β-Aziridinyl-pregn-5-en-3β-ol is one of the comparison compounds listed.
Helvetica Chimica Acta 34, 756-767 (1951) discloses reaction schemes according to which to 20α- and 20β-stereoisomers of 17,20-epoxy-17α-allopregnane-3β,21-diol diacetate may be formed.
In the Journal of Medicinal Chemistry 10(4), 546-551 (1967), the steroidal cyclic ether of formula 5 below is mentioned as an intermediate in the preparation of steroidal compounds having antiestrogenic properties.

Tetrahedron 29, 883-889 (1973) discloses certain steroid synthetic pathways in which (3β,17β)-3′-ethynyl spiro[androst-5-ene-17,2′oxiran]-3-ol acetate and (3β,17β)-3′-[(trimethylsilyl)ethynyl]spiro[androst-5-ene-17,2′ oxiran]-3-ol acetate are intermediates.
Tetrahedron 43, 631-641 (1987) describes the preparation of the compounds of formula 6 and 7 below, as well as their 5α-H analogues.
